Is CAD p.Ile680Val (c.2038A>G) pathogenic?

CAD p.Ile680Val (c.2038A>G) is classified Uncertain significance in CAD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-14). AlphaMissense: likely benign (0.1977); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with CAD p.Ile680Val (c.2038A>G)?

CAD p.Ile680Val (c.2038A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CAD p.Ile680Val (c.2038A>G) in the general population?

CAD p.Ile680Val (c.2038A>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CAD p.Ile680Val (c.2038A>G)?

AlphaMissense predicts likely benign (score 0.1977) — an in-silico prediction, not a clinical call.

CAD p.Ile680Val

c.2038A>G · rs1270960913 · VCV1444893

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1977	likely benign
REVEL	0.619	indeterminate
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.5, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 7,481 bp · p 8.7e-11 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,092 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00105% 17/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
South Asiangrpmax	0.00549%	18,218
East Asian	0.00223%	44,894
European (non-Finnish)	0.000169%	589,998

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CAD
Protein: p.Ile680Val
Coding: c.2038A>G
MANE Select: NM_004341
dbSNP: rs1270960913
Type: single nucleotide variant
Location: chr2:27226531 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 680: the atp-grasp 1 domain; the 'cpsase (carbamoyl phosphate synthase)' region; the 'cpsase a' region

Full CAD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAD c.6480+6T>C Uncertain significance ★★ same condition
CAD p.Ala1527Thr Uncertain significance ★★ ⚠ same condition
CAD p.Ala1769Thr Uncertain significance ★★ ⚠ same condition
CAD p.Ala1824Ser Uncertain significance ★★ ⚠ same condition
CAD p.Ala495Pro Uncertain significance ★★ ⚠ same condition
CAD p.Ala608Thr Uncertain significance ★★ ⚠ same condition
CAD p.Arg1075His Uncertain significance ★★ ⚠ same condition
CAD p.Arg1181Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cad-p-ile680val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown